EP0181442A1 - Procédé de préparation de dérivés du prégnane - Google Patents

Procédé de préparation de dérivés du prégnane Download PDF

Info

Publication number
EP0181442A1
EP0181442A1 EP85110247A EP85110247A EP0181442A1 EP 0181442 A1 EP0181442 A1 EP 0181442A1 EP 85110247 A EP85110247 A EP 85110247A EP 85110247 A EP85110247 A EP 85110247A EP 0181442 A1 EP0181442 A1 EP 0181442A1
Authority
EP
European Patent Office
Prior art keywords
chloroethynyl
general formula
group
nitrooxy
androsten
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP85110247A
Other languages
German (de)
English (en)
Other versions
EP0181442B1 (fr
Inventor
Helmut Dr. Hofmeister
Klaus Dr. Annen
Henry Dr. Laurent
Rudolf Prof. Wiechert
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to AT85110247T priority Critical patent/ATE44532T1/de
Publication of EP0181442A1 publication Critical patent/EP0181442A1/fr
Application granted granted Critical
Publication of EP0181442B1 publication Critical patent/EP0181442B1/fr
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
    • C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom

Definitions

  • the invention relates to the subject matter characterized in the claims.
  • 17 ⁇ -ethynyl-17 ⁇ -nitrooxy steroids produced by ethynylation of 17-oxosteroids and esters of the 17a-ethynyl-17 ⁇ -hydroxysteroids formed with nitric acid in acetic anhydride
  • 17 ⁇ -acetyl-17 ⁇ -formyl steroids Chem. Ber. 111, 1978, 3086-3096.
  • These compounds could be converted by means of known methods into Pregnan derivatives of the general formula I according to claim 1, the further conversion of which into pharmacologically active steroids is well known.
  • the first stage of the process according to the invention can be carried out under the conditions which are usually used for the esterification of tertiary or sterically hindered steroid alcohols with nitric acid, trifluoroacetic acid or trichloroacetic acid.
  • the esterification with trifluoroacetic acid or trichloroacetic acid can be carried out, for example, under completely conventional conditions using the corresponding trihaloacetyl chlorides or hexahalacetic anhydrides in the presence of bases such as pyridine.
  • bases such as pyridine.
  • the mixture required for this can be prepared, for example, from the components (J. Amer. Chem. Soc., 82, 1960, 3588-3598).
  • Nitric acid containing about 70 to 100 percent by weight of acid is suitable.
  • the reaction is usually carried out at a reaction temperature of from -50 ° C. to + 0 ° C., preferably from -30 ° C. to 10 ° C.
  • the response time is usually 10 to 120 minutes.
  • the second reaction step can be carried out under the conditions described in the above-mentioned publications or variations thereof, as set out in US Pat. No. 4,102,908. These process conditions are not particularly suitable for commercial implementation, since the necessary treatment of the waste containing mercury (II) salts is quite complex. It is much easier to carry out this reaction step using silver (I) salts as a catalyst. It is surprising in two respects that the reaction step proceeds in the desired manner under these conditions. Based on the information in the publication in Chem Ber. on the one hand, one should have expected that when silver (I) salts were used, the ethynyl group would not be hydrated. On the other hand, it was feared that the chlorine atom of the starting product or end product would be split off and render the silver catalyst ineffective by the formation of silver chloride.
  • Well dissociating silver (I) salts such as silver (I) nitrate, silver (I) acetate, silver (I) fluoride or silver (I) sulfate are preferably used as catalysts for this process step. which are preferably used in a concentration of 0.01 to 0.5 mol% based on the steroid.
  • This reaction step is preferably carried out using concentrated formic acid containing 95 to 100 percent by weight acid.
  • this reaction step proceeds more uniformly if an additional dipolar aprotic or basic solvent is added to the reaction mixture.
  • Suitable additives are, for example, tertiary amines, such as triethylamine or N-methylmorpholine or dipolar aprotic solvents containing amide groups, such as dimethylformamide, N-methylacetamide or in particular hexamethylphosphoric triamide or 1-methyl-2-pyrrolidone. Good results are generally obtained if 10 to 50% of this solvent, based on the other components, is added to the reaction mixture.
  • This reaction stage is usually carried out at a temperature of 0 ° C to 150 ° C.
  • the optionally subsequent saponification of the 17-formyl esters takes place under the conditions which are well known to the person skilled in the art.
  • the saponification of these compounds in a water-containing lower alcohol methanol, ethanol, propanol or isopropanol
  • basic catalysts for example the corresponding sodium alcoholate or potassium alcoholate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or potassium hydrogen carbonate
  • reaction temperature usually a temperature between 0 ° C and the boiling point of the solvent.
  • the subsequent subsequent exchange of the 21-chlorine atom for an alkanoyloxy group also takes place under conventional conditions, for example by reacting the compounds in an inert solvent with the corresponding sodium or potassium alkanoate.
  • Suitable solvents are, for example, lower ketones, such as acetone, methyl ethyl ketone or methyl isobutyl ketone or dipolar aprotic solvents such as dimethylformamide, N-methylacetamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidone or hexamethylphosphoric acid triamide.
  • the reaction is usually carried out at a temperature of 50 ° C to 120 ° C.
  • the optionally subsequent saponification of the 21-alkanoyloxy compounds can be carried out under the same conditions as the saponification of the 17-formyl compounds.
  • the starting compounds for the process according to the invention are known and can be synthesized, for example, by known methods (Chem. Soc., 1962, 4995).
  • the resulting crude product is mixed with 0.3 ml of 70% perchloric acid in 30 ml of acetone at room temperature. After 30 minutes, the reaction mixture is poured into ice water, the precipitated product is filtered off, dissolved in ethyl acetate, washed with water and dried over sodium sulfate. After chromatography of the crude product on silica gel with a hexane-ethyl acetate gradient, 6.0 g of 17a-chloroethynyl-17 ⁇ -hydroxy-4,9 (11) -androstadien-3-one are obtained. Melting point 157.1 ° C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Glass Compositions (AREA)
  • Paper (AREA)
  • Sewage (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP85110247A 1984-09-17 1985-08-16 Procédé de préparation de dérivés du prégnane Expired EP0181442B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT85110247T ATE44532T1 (de) 1984-09-17 1985-08-16 Verfahren zur herstellung von pregnan-derivaten.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3434448 1984-09-17
DE19843434448 DE3434448A1 (de) 1984-09-17 1984-09-17 Verfahren zur herstellung von pregnan-derivaten

Publications (2)

Publication Number Publication Date
EP0181442A1 true EP0181442A1 (fr) 1986-05-21
EP0181442B1 EP0181442B1 (fr) 1989-07-12

Family

ID=6245838

Family Applications (1)

Application Number Title Priority Date Filing Date
EP85110247A Expired EP0181442B1 (fr) 1984-09-17 1985-08-16 Procédé de préparation de dérivés du prégnane

Country Status (15)

Country Link
US (2) US4708823A (fr)
EP (1) EP0181442B1 (fr)
JP (1) JPH0710877B2 (fr)
AT (1) ATE44532T1 (fr)
CA (1) CA1260929A (fr)
CS (1) CS250695B2 (fr)
DD (1) DD238387A5 (fr)
DE (2) DE3434448A1 (fr)
DK (1) DK420985A (fr)
ES (1) ES8604987A1 (fr)
FI (1) FI853560L (fr)
GR (1) GR852241B (fr)
HU (1) HU194905B (fr)
PL (1) PL255391A1 (fr)
SU (1) SU1440351A3 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995030684A1 (fr) * 1994-05-09 1995-11-16 Pharmacia & Upjohn Company SYNTHESE DU 17β-CYANO-3-ETHOXY-17α-HYDROXY-6-METHYLANDROSTA-3,5,9(11)-TRIENE

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU7556291A (en) * 1990-03-27 1991-10-21 Schering Corporation Process for 9alpha-hydroxy steroid dehydration
AP141A (en) * 1990-04-25 1991-08-25 Richter Gedeon Vegyeszet Novel steroid doils.
JPH10191658A (ja) * 1996-01-09 1998-07-21 Nikon Corp 振動アクチュエータ
US5879711A (en) * 1997-11-07 1999-03-09 Sequeira; Joel A. Stable antiandrogenic gel composition
US6696592B2 (en) 2001-05-22 2004-02-24 Nicox-S.A. Methods of making 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivatives and intermediates useful in the synthesis thereof
CN103833814A (zh) * 2014-03-06 2014-06-04 浙江仙居君业药业有限公司 17羟基-孕甾-4-烯-3,20-二酮-21-醋酸酯的制备方法
CN105017364A (zh) * 2015-07-06 2015-11-04 湖南新合新生物医药有限公司 甲基泼尼松龙中间体及其制备方法和应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3067214A (en) * 1960-04-20 1962-12-04 Merck & Co Inc Haloethisterone compounds
DE2625306B1 (de) * 1976-06-02 1977-11-03 Schering Ag, 1000 Berlin Und 4619 Bergkamen Verfahren zur Herstellung von Pregnan-Derivaten
US4342702A (en) * 1981-05-18 1982-08-03 The Upjohn Company Metallated halogenated acetylene corticoid synthesis
EP0063368A1 (fr) * 1981-04-16 1982-10-27 Richter Gedeon Vegyeszeti Gyar R.T. Procédé de préparation de dérivés du pregn-4-ène-3,20-dione, ainsi que les dérivés du 17-alpha-éthynyl-17-bêta-trifluoroacétoxy-gon-4-ène-3-one et médicaments contenant ces derniers
EP0123241A1 (fr) * 1983-04-25 1984-10-31 Schering Aktiengesellschaft Procédé de préparation de dérivés du Prégnane

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU185797B (en) * 1981-04-16 1985-03-28 Richter Gedeon Vegyeszet Process for producing 3-oxo-17-alpha-ethinyl-17beta-trifluoroacetoxy-gonane derivatives
HU183397B (en) * 1981-04-16 1984-04-28 Richter Gedeon Vegyeszet Process for preparing 17alpha-hydroxy-pregn-4-ene-3,20-dione derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3067214A (en) * 1960-04-20 1962-12-04 Merck & Co Inc Haloethisterone compounds
DE2625306B1 (de) * 1976-06-02 1977-11-03 Schering Ag, 1000 Berlin Und 4619 Bergkamen Verfahren zur Herstellung von Pregnan-Derivaten
EP0063368A1 (fr) * 1981-04-16 1982-10-27 Richter Gedeon Vegyeszeti Gyar R.T. Procédé de préparation de dérivés du pregn-4-ène-3,20-dione, ainsi que les dérivés du 17-alpha-éthynyl-17-bêta-trifluoroacétoxy-gon-4-ène-3-one et médicaments contenant ces derniers
US4342702A (en) * 1981-05-18 1982-08-03 The Upjohn Company Metallated halogenated acetylene corticoid synthesis
EP0123241A1 (fr) * 1983-04-25 1984-10-31 Schering Aktiengesellschaft Procédé de préparation de dérivés du Prégnane

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMISCHE BERICHTE, Band 111, Nr. 9, September 1978, Seiten 3086-3093, Weinheim, DE; H. HOFMEISTER et al.: "Überführung von 17alpha-Ethinyl-17beta-nitrooxy-Steroiden in 17alpha-Hydroxy-20-oxopregnan-Derivate" *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995030684A1 (fr) * 1994-05-09 1995-11-16 Pharmacia & Upjohn Company SYNTHESE DU 17β-CYANO-3-ETHOXY-17α-HYDROXY-6-METHYLANDROSTA-3,5,9(11)-TRIENE

Also Published As

Publication number Publication date
HUT38951A (en) 1986-07-28
DE3434448A1 (de) 1986-03-27
DK420985A (da) 1986-03-18
JPS61129197A (ja) 1986-06-17
ATE44532T1 (de) 1989-07-15
CS250695B2 (en) 1987-05-14
PL255391A1 (en) 1986-07-15
ES8604987A1 (es) 1986-03-16
HU194905B (en) 1988-03-28
GR852241B (fr) 1986-01-17
FI853560A0 (fi) 1985-09-17
DD238387A5 (de) 1986-08-20
FI853560L (fi) 1986-03-18
DE3571441D1 (en) 1989-08-17
US4956482A (en) 1990-09-11
US4708823A (en) 1987-11-24
CA1260929A (fr) 1989-09-26
DK420985D0 (da) 1985-09-17
EP0181442B1 (fr) 1989-07-12
ES546995A0 (es) 1986-03-16
JPH0710877B2 (ja) 1995-02-08
SU1440351A3 (ru) 1988-11-23

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